This grant introduces the novel concept that changes in lung lipid metabolism contribute to the development of acute lung injury after chronic alcohol exposure. Recently published findings indicate that chronic alcohol consumption induces severe metabolic changes in the lung including decreased AMP activated protein kinase (AMPK) activation, increased lipid synthesis and impaired beta-oxidation of fatty acids. Collectively, these changes are associated with marked lipid (triglyceride and free fatty acid) accumulation; a phenotype that we have coined the alcoholic fatty lung. Furthermore, we present data linking these metabolic changes to immune impairments in the alcohol exposed lung leading us to propose the central hypothesis of this application that lung lipid changes play a causal role in the development of alcohol-related inflammatory lung diseases. Studies in Aim 1 will perform a detailed examination of the effects of alcohol on lung lipid homeostasis in the surfactant producing cells (alveolar epithelial type II cells) of the distal epithelium. In addition, we will elucidate the mechanisms leading to alcohol-induced decreases in AMPK activation and determine whether activators or inhibitors of AMPK modulate alcohol's effects on lipid homeostasis in alveolar epithelial type II cells in culture. In Aim 2, we will perform in vivo studes to determine whether drugs modifying AMPK activation influence alcohol's effects on lung lipid homeostasis and susceptibility to developing acute lung injury. Finally in Aim 3, we will test whether specific inhibitors of lipid synthesizing enzymes attenuates alcohol-related lung lipid accumulation and decreases susceptibility to developing acute lung injury. For these latter studies, we will selectively inhibit fatty acid synthase (FAS) and diacylglycerol acyltransferase 1 (DGAT1), two enzymes found to be significantly up-regulated in the chronic alcohol exposed rat lung. The overarching goal of this program is to further elucidate the molecular mechanisms leading to alcohol-induced lung lipid dysregulation and to provide the foundation for future investigations testing whether treatments aimed at suppressing metabolic changes in lung are effective for treating alcohol-related inflammatory lung conditions.